Cell Polarization and Epigenetic Status Shape the Heterogeneous Response to Type III Interferons in Intestinal Epithelial Cells, Bhushal et al. (2017)

[jnmaciuch]

Cell Polarization and Epigenetic Status Shape the Heterogeneous Response to Type III Interferons in Intestinal Epithelial Cells
Authors:
Sudeep Bhushal, Markus Wolfsmüller, Tharini A. Selvakumar, Lucas Kemper, Dagmar Wirth, Mathias W. Hornef, Hansjrg Hauser, Mario Kster

Abstract [paragraph breaks added]:
Type I and type III interferons (IFNs) are crucial components of the first-line antiviral host response. While specific receptors for both IFN types exist, intracellular signaling shares the same Jak-STAT pathway. Due to its receptor expression, IFN-λ responsiveness is restricted mainly to epithelial cells.

Here, we display IFN-stimulated gene induction at the single cell level to comparatively analyze the activities of both IFN types in intestinal epithelial cells and mini-gut organoids. Initially, we noticed that the response to both types of IFNs at low concentrations is based on a single cell decision-making determining the total cell intrinsic antiviral activity. We identified histone deacetylase (HDAC) activity as a crucial restriction factor controlling the cell frequency of IFN-stimulated gene (ISG) induction upon IFN-λ but not IFN-β stimulation. Consistently, HDAC blockade confers antiviral activity to an elsewise non-responding subpopulation.

Second, in contrast to the type I IFN system, polarization of intestinal epithelial cells strongly enhances their ability to respond to IFN-λ signaling and raises the kinetics of gene induction. Finally, we show that ISG induction in mini-gut organoids by low amounts of IFN is characterized by a scattered heterogeneous responsiveness of the epithelial cells and HDAC activity fine-tunes exclusively IFN-λ activity.

This study provides a comprehensive description of the differential response to type I and type III IFNs and demonstrates that cell polarization in gut epithelial cells specifically increases IFN-λ activity.

Link | PDF (Frontiers in Immunology, Open Access)

 

[jnmaciuch]

I'm interested in this study because I am exploring possible epigenetic mechanisms by which an interferon response could be sustained in ME/CFS. Before this study, it was already known that some cells are more prone to inducing an interferon response to protect against viral infections than others--even within the same cell culture, only a fraction of infected cells may mount an interferon response.

This study confirms that cells can individually adopt different stable epigenetic states that make them more or less likely to produce an interferon response under stimulation. Furthermore, it confirms that this epigenetic regulation is primarily mediated by histone de-acetylases (HDACs), which are one class of epigenetic modifications on DNA.

Histone de-acetylation also came up as very important in mediating the resolution of an interferon response in this paper:

Thread 'Inhibition of Histone Deacetylation Induces Constitutive Derepression of the Beta Interferon Promoter [...] , 2001, Shestakova et al.'

Jun 28, 2025

Inhibition of Histone Deacetylation Induces Constitutive Derepression of the Beta Interferon Promoter and Confers Antiviral Activity​

Elena Shestakova, Marie-Thérèse Bandu, Janine Doly, Eliette Bonnefoy

Abstract
[Paragraph breaks added]
The induction of alpha/beta interferon (IFN-α/β) genes constitutes one of the first responses of the cell to virus infection. The IFN-β gene is constitutively repressed in uninfected cells and is transiently activated after virus infection. In this work we demonstrate that histone deacetylation regulates the silent state of the murine IFN-β...

• jnmaciuch
• interferon
• Replies: 17
• Forum: Other health news and research

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All in all, this shows that there exist epigenetic mechanisms that can alter parts of the cellular interferon response in longer time frames. The fact that cells in the same culture can display different states downstream of this epigenetic mechanism means that this mechanism must be highly accessible and modifiable--unlike some other epigenetic changes associated with more permanent phenotypic differences like maturation/development into certain types of cells. If interferons are relevant in ME/CFS, these epigenetic mechanisms are a good place to look.

 

[Creekside]

FWIW, my ME symptoms started as a type IV food sensitivity, which would involved t-cells and IFN-g. Symptoms would abruptly flare up 48 hrs after eating something, +/- just a few minutes. I lost that response after food poisoning, but that loss of IFN-g signalling didn't change my baseline symptoms. They would flare up shortly (20 minutes?) after starting a meal; I think that was an insulin/tryptophan response, since taking BCAAs with the meal would block or slow down and spread out the response.

My PEM seemed to be triggered by physical activities that damaged muscles, which fits IFN-g rising 24 hrs later. Avoiding such activities didn't reduce my baseline ME symptoms. So, my experience doesn't seem to support abnormal IFN production as the mechanism of the ME state. It does cause an increase over baseline.

I also tried a strong t-cell suppressor (cyclosporin), which had no noticeable effect on my symptoms (I'm not sure whether I triggered PEM during that experiment). Would that be counterevidence to IFN response being the ME mechanism?

Also, would a sustained IFN response be capable of switching state abruptly (over the space of minutes)?

 

[jnmaciuch]

Also, would a sustained IFN response be capable of switching state abruptly (over the space of minutes)?

Sorry, to clarify, it’s not a sustained interferon response per se, it’s a sustained epigenetic state which involves parts of the downstream interferon response (some of which are themselves “mediators” of the full interferon response when the receptor is activated). The hypothesized mechanism would lead to some specific interferon-stimulated genes being somewhat upregulated at baseline without necessarily the whole pathway being constantly “on”. But depending on the specific epigenetic change, it could absolutely prime cells to have an exacerbated response to transient stimulation of the full interferon response.

Would that be counterevidence to IFN response being the ME mechanism?

From everything I’ve looked into, it makes more sense to me to construct a story around other types of interferon rather than interferon gamma, so I’m not particularly convinced that T cells need to be playing a role at all.

Interestingly I’ve been trying to find anyone who happened to try Cyclosporin because it is supposed to work by blocking a specific mitochondrial pore (important in T cell function), and I was hypothesizing that mtDNA release during exertion in tissue cells through that pore triggers a transient exacerbated interferon response leading to PEM.

But since you mention that you don’t get PEM symptoms from exertion on its own but rather from suspected damage to muscle tissue, that would ironically make you the least likely person to show a response to Cyclosporin even if I was proven right about the mechanism in more typical cases of ME/CFS. However, the other half of the interferon response I’m hypothesizing is the part that responds to cytosolic or extracellular DNA—that would also be triggered by free floating DNA from damaged cells.